S155: EFFICACY AND SAFETY RESULTS FROM ASCEMBL, A PHASE 3 STUDY OF ASCIMINIB VS BOSUTINIB IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE AFTER ≥2 PRIOR TYROSINE KINASE INHIBITORS: WK 96 UPDATE
Authors: D. Rea, A. Hochhaus, M. J. Mauro, Y. Minami, E. Lomaia, S. Voloshin, A. Turkina, D.-W. Kim, J. F. Apperley, J. E. Cortes, A. Abdo, L. M. Fogliatto, D. D. H Kim, P. le Coutre, S. Saussele, M. Annunziata, T. P. Hughes, N. Chaudhri, L. Chee, V. García-Gutiérrez, K. Sasaki, S. Kapoor, A. Allepuz, S. Quenet, V. Bédoucha, C. Boquimpani
Journal: HemaSphere (2022)

Background: Asciminib is the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL primary analysis, asciminib had superior efficacy and better safety/tolerability vs bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior tyrosine kinase inhibitors (TKIs). Major molecular response (MMR) rate at wk 24 was 25.5% on asciminib vs 13.2% on BOS; the difference in MMR rates after adjusting for baseline major cytogenetic response (MCyR) was 12.2% (95% CI, 2.19%-22.30%; 2-sided P=.029). Fewer grade ≥3 adverse events (AEs) and AEs leading to treatment discontinuation occurred on asciminib vs BOS. After a median follow-up of 2.3 years (16.5 months' additional follow-up since the primary analysis), we report updated efficacy and safety results (cutoff: October 6, 2021). Aims: The key secondary objective was to compare MMR rate at wk 96 on asciminib vs BOS. Methods: Eligible pts provided informed consent, were adults with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 European LeukemiaNet recommendations. They were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by baseline MCyR status (Ph+ metaphases ≤35%). Results: 233 pts were randomized to asciminib (n=157) or BOS (n=76). At cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) pts, respectively; the most common reason for discontinuation was lack of efficacy in 38 (24.2%) and 27 (35.5%) pts, respectively. MMR rate at wk 96 (per ITT) was 37.6% on asciminib and 15.8% on BOS, meeting the key secondary objective. The difference after adjusting for baseline MCyR was 21.7% (95% CI, 10.5%-33.0%; 2-sided P=.001). Preplanned subgroup analyses showed that MMR rate at wk 96 was consistently higher with asciminib than BOS in all demographic and prognostic subgroups, including all prior lines of TKI therapy, and regardless of the reason for discontinuation of the last TKI (Figure). At wk 96, more pts on asciminib than BOS had BCR::ABL1IS ≤1% (45.1% vs 19.4%) (Table). Responses were durable, with a probability (95% CI) of maintaining MMR and BCR::ABL1IS ≤1% for ≥72 wk of 96.7% (87.4%-99.2%) and 94.6% (86.2%-97.9%), respectively, on asciminib and 92.9% (59.1%-99.0%) and 95.0% (69.5%-99.3%), respectively, on BOS. Median time to treatment failure was 24 months on asciminib and 6 months on BOS. Median duration (range) of exposure was 103.1 (0.1-201.1) wk on asciminib and 30.5 (1.0-188.3) wk on BOS. Despite asciminib's longer duration of exposure, its safety/tolerability continued to be better than that of BOS (Table). Fewer pts on asciminib than BOS had AEs leading to treatment discontinuation (7.7% vs 26.3%). No new on-treatment deaths were reported since the primary analysis. Most frequent (>10%) grade ≥3 AEs on asciminib vs BOS were thrombocytopenia (22.4%, 9.2%), neutropenia (18.6%, 14.5%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). Image:Summary/Conclusion: After >2 years of follow-up, asciminib continued to show clinically and statistically significant, superior efficacy and better safety/tolerability vs BOS. Responses were durable, and MMR was more than double on asciminib than BOS. The difference in MMR rates between the 2 arms increased from 12.2% at wk 24 to 21.7% at wk 96. A higher proportion of pts had BCR::ABL1IS ≤1%, a milestone response in later lines that is associated with improved long-term survival. These results further support the use of asciminib as a new CML therapy, with the potential to transform standard of care.